Chronic myelogenous leukemia (CML) originates from leukemia stem cells (LSCs) harboring the BCR-ABL1 fusion oncogene, a constitutively active tyrosine kinase (reviewed in Kavalerchik et al. J Clin Oncol (2008) 26, 2911-2915; Lugo et al. (1990) Science 247, 1079-1082). The introduction of imatinib, a tyrosine kinase inhibitor (TKI) targeting BCR-ABL1, has transformed the clinical approach to the management of CML and dramatically improved the patient outcome (Druker et al. N Engl J Med (2001) 344, 1038-1042; Druker et al. (2001) N Engl J Med 344, 1031-1037; and Baccarani et al. (2006) Blood 108, 1809-1820).
Nonetheless, a cure for CML remains elusive. Many patients with advanced disease fail to achieve sustainable long term remission primarily because of the emergence of disease-initiating LSCs that are resistant to TKIs despite BCR-ABL1 inhibition (Corbin, A. S., et al. (2011) J Clin Invest 121, 396-409). Thus, interruption of TKI treatment leads to a relapse of the disease whereas patients receiving TKI treatment over an extended period of time have a significant risk of acquiring TKI-resistant CML that can progress to acute leukemia (Faderl, S., et al. (1999) N Engl J Med 341, 164-172).
Accordingly, there is an urgent need in the art for methods and compositions that can be used to treat chronic myelogenous leukemia, including TKI-resistant chronic myelogenous leukemia.